Substituted pyrimidines and methods of use

Abstract

The present disclosure provides inhibitors of activin receptor-like kinase 5 (ALK5). Also disclosed are methods to modulate the activity of ALK5 and methods of treatment of disorders mediated by ALK5.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A is selected from phenyl, 5- to 6-membered heteroaryl, indanyl, indazolyl, benzotriazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzodioxanyl, and tetrahydrobenzazepinyl; 
 B is selected from phenyl and 5- to 6-membered heteroaryl; 
 R A  is independently selected at each occurrence from:
 halogen, —OR 1 , —N(R 1 ) 2 , —S(═O) 2 R 1 , —S(═O) 2 N(R 1 ) 2 , —S(═O) 2 NR 2 R 3 , —NR 1 S(═O) 2 R 1 , —NR 1 S(═O) 2 N(R 1 ) 2 , —C(O)R 1 , —C(O)OR 1 , —NR 1 C(O)R 1 , —NR 1 C(O)N(R 1 ) 2 , —C(O)N(R 1 ) 2 , —C(O)NR 2 R 3 ; 
 C 1-6  alkyl and —N(R 1 )—C 1-10  alkyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from —OR 1 , —N(R 1 ) 2 , —C(O)OR 1 , C 3-8  carbocycle, and 3- to 10-membered heterocycle; and 
 C 3-8  carbocycle and 3- to 10-membered heterocycle, 
 wherein each C 3-8  carbocycle and 3- to 10-membered heterocycle in R A  is independently optionally substituted with one or more substituents selected from —OR 1 , —CH 2 N(R 1 ) 2 , —N(R 1 ) 2 , —C(O)R 1 , —CH 2 C(O)OR 1 , —C(O)OR 1 , —C(O)N(R 1 ) 2 , R 1 , and C 1-6  alkyl; 
 
 R B  is independently selected at each occurrence from halogen, —CN, —NH 2 , —NHCH 3 , —NHCH 2 CH 3 , —C(O)CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 F, —CHF 2 , —CF 3 , C 3-4  carbocycle, and 3- to 4-membered heterocycle; 
 m is 0, 1 or 2; 
 n is 0, 1, 2, or 3; 
 R 1  is independently selected at each occurrence from hydrogen; and C 1-6  alkyl, 1- to 6-membered heteroalkyl, C 0-3  alkyl-(C 3-8  carbocycle), and C 0-3  alkyl-(3- to 10-membered heterocycle), each of which is optionally substituted by one or more substituents selected from —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —C(O)CH 3 , —C(O)OH, —C(O)NH 2 , ═O, —OH, —CH 2 OH, —CH 2 CH 2 OH, —OCH 3 , —OCH 2 CH 3 , —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , C 3-8  carbocycle, and 3- to 6-membered heterocycle; and 
 R 2  and R 3  are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 1 . 
 
     
     
         2 .- 3 . (canceled) 
     
     
         4 . The compound or salt of  claim 1 , wherein A is selected from phenyl and 5- to 6-membered heteroaryl. 
     
     
         5 . The compound or salt of  claim 1 , wherein A is selected from phenyl, indanyl, thiazolyl, thiophenyl, pyrazolyl, pyridyl, pyrimidinyl, indazolyl, benzotriazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzodioxanyl, and tetrahydrobenzazepinyl. 
     
     
         6 . The compound or salt of  claim 1 , wherein A is phenyl. 
     
     
         7 . The compound or salt of  claim 1 , wherein the compound is a compound of Formula (I-B): 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound or salt of  claim 1 , wherein the compound is a compound of Formula (I-C): 
       
         
           
           
               
               
           
         
       
     
     
         9 .- 10 . (canceled) 
     
     
         11 . The compound or salt of  claim 1 , wherein R A  is independently selected at each occurrence from:
 halogen, —OR 1 , —N(R 1 ) 2 , —S(═O) 2 R 1 , —S(═O) 2 N(R 1 ) 2 , —NR 1 S(═O) 2 R 1 , —NR 1 S(═O) 2 N(R 1 ) 2 , —C(O)R 1 , —C(O)OR 1 , —NR 1 C(O)R 1 , —NR 1 C(O)N(R 1 ) 2 , —C(O)N(R 1 ) 2 ;   C 1-6  alkyl and —N(R 1 )—C 1-10  alkyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from —OR 1 , —N(R 1 ) 2 , and 3- to 10-membered heterocycle; and   3- to 10-membered heterocycle,   wherein each 3- to 10-membered heterocycle in R A  is independently optionally substituted with one or more substituents selected from —OR 1 , —N(R 1 ) 2 , —C(O)R 1 , —CH 2 C(O)OR 1 , —C(O)OR 1 , —C(O)N(R 1 ) 2 , and R 1 .   
     
     
         12 .- 13 . (canceled) 
     
     
         14 . The compound or salt of  claim 1 , wherein R A  is —NR 1 C(O)R 1 . 
     
     
         15 . The compound or salt of  claim 1 , wherein R A  is —C(O)OR 1 . 
     
     
         16 . The compound or salt of  claim 1 , wherein R A  is C 1-6  alkyl substituted with 4- to 8-membered heterocycle, wherein the 4- to 8-membered heterocycle is substituted with —C(O)OR 1 . 
     
     
         17 .- 21 . (canceled) 
     
     
         22 . The compound or salt of  claim 1 , wherein m is 1. 
     
     
         23 . (canceled) 
     
     
         24 . The compound or salt of  claim 1 , wherein B is selected from phenyl and pyridyl. 
     
     
         25 . (canceled) 
     
     
         26 . The compound or salt of  claim 1 , wherein B is 2-pyridyl. 
     
     
         27 . (canceled) 
     
     
         28 . The compound or salt of  claim 1 , wherein R B  is independently selected at each occurrence from halogen, —OH, —CH 3 , and —CHF 2 . 
     
     
         29 . The compound or salt of  claim 1 , wherein R B  is —CH 3 . 
     
     
         30 . (canceled) 
     
     
         31 . The compound or salt of  claim 1 , wherein n is 1. 
     
     
         32 . (canceled) 
     
     
         33 . The compound or salt of  claim 1 , wherein the compound is a compound of Formula (I-E): 
       
         
           
           
               
               
           
         
       
     
     
         34 .- 40 . (canceled) 
     
     
         41 . A pharmaceutical composition comprising the compound or salt of  claim 1  a pharmaceutically acceptable carrier. 
     
     
         42 .- 43 . (canceled) 
     
     
         44 . A method of treating an ALK5-mediated disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of the compound or salt of  claim 1 . 
     
     
         45 . (canceled) 
     
     
         46 . The method of  claim 44 , wherein the disease or condition is fibrosis. 
     
     
         47 .- 50 . (canceled) 
     
     
         51 . The method of  claim 46 , where the fibrosis is idiopathic pulmonary fibrosis (IPF). 
     
     
         52 . The method of  claim 46 , wherein the fibrosis is intestinal fibrosis. 
     
     
         53 . (canceled) 
     
     
         54 . The method of  claim 44 , wherein the disease or condition is selected from breast cancer, colon cancer, prostate cancer, lung cancer, hepatocellular carcinoma, glioblastoma, melanoma, and pancreatic cancer. 
     
     
         55 .- 63 . (canceled)